KR840000864B1 - Process for preparing analogs of prostacyclin - Google Patents

Abstract

Compds. of the general formula I (where R1=a staright or branched alkyl residue with <=6C atoms, a straight or branched aliph. hydrocarbon residue with 3-6 C atoms, a cycloaliph. hydrocarbon residue with 3-7 C atoms, an araliph. hydrocarbon residue with 7-9 C atoms, or a physiol compatible metal, NH4, or ammonium ion derived from a primary or tertiary amine or a tetraalkylammonium ion; and R2=a cycloalkyl residue with 3-7 C atoms or a straight or branched alkyl residue with <=8 C atoms, which could also be substituted with ahlogen, an α- or α-thienyl residue, an α- or β-furyl residue, an oxyphenyl, or an α- or β-oxythienyl residue) were prepd. and tested for blood pressure-lowering activity in rats, bovine coronary artery relaxation activity, and blood platelet aggregation activity.

Description

Method for preparing prostacyclin homologue

The present invention relates to a process for the preparation of the phosphocycline homologue of the general formula (I) having a more specific action and / or longer duration than PGI ₂ .

In the above formula,

R ¹ is hydrogen, a straight or branched chain alkyl group of up to 6 carbon atoms, a straight or branched chain unsaturated aliphatic hydrocarbon group of 3 to 6 carbon atoms, an alicyclic hydrocarbon of 3 to 7 carbon atoms, an araliphatic hydrocarbon of 7 to 9 carbon atoms, or physiologically acceptable Metal ions or ammonium ions, or ammonium ions or tetraalkylammonium ions derived from primary, secondary or tertiary amines,

R ² is a cycloalkyl group having 3 to 7 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms wherein these alkyl groups are (a) halogen or halogen, trifluoromethyl and / or alkyl or alkoxy having 1 to 6 carbon atoms. Mono-, di- or tri-substituted α- or β-thienyl groups or α- or βfuryl groups or (b) halogen, trifluoromethyl and / or alkyl or alkoxy of 1 to 6 carbon atoms in the nucleus -, May be substituted with an oxyphenyl group or an α- or β-oxythienyl group which may be di- or trisubstituted.

Recently isolated, prostacycline or PGI2, a naturally occurring substance in the prostaglandin family, is characterized by an excellent inhibitory effect on thromvosite aggregation (The Lanct 1977, 18).

,3.1977)]을 이완시키므로, 혈전증 및 경색의 예방과 치료에 사용할 수 있다.In addition, PGI ₂ can be used in various blood vessels (eg, coronary arteries (Prostaglandins).

, 3.1977), which can be used for the prevention and treatment of thrombosis and infarction.

The present invention provides a process for preparing a compound of formula (III) by a) ring closing a compound of formula (II) in the presence of a suitable electrophilic reagent, wherein a ₁ ) R ³ and / or R ⁴ in formula (III) Is a protecting group, optionally removing this group to give a compound of formula III wherein R ³ and R ⁴ are hydrogen,

b) Hx is removed from the compound of formula III to give a compound of formula IV

c) when R ³ and / or R ⁴ in the compound of formula (IV) is not a hydrogen and a protecting group, the group is removed under suitable neutral or alkaline conditions to give the compound of formula (I),

c1) if necessary, when R ³ and / or R ⁴ is not hydrogen and is a protecting group, the group is removed simultaneously from Hb from general formula (III) with HX to give a compound of general formula (I),

d) if necessary, esterifying a compound of formula (I) wherein R ¹ is hydrogen or a cation and R2 is as described above to give a compound of formula (I) wherein R ¹ is an alkyl group,

f) In compounds of formula (I) wherein R ¹ is a physiologically soluble metal ion or NH ₄ ion, or ammonium ion derived from primary, secondary and tertiary amines, the cation R ¹ may be It is related with the method of manufacturing the prostacyclin derivative of general formula (I) by substituting for.

In the above general formula

R ¹ and R ² are as defined above,

R ³ and R ⁴ are the same or different and represent hydrogen or an easily removable protecting group,

X represents chlorine, bromine or iodine. Among the substituents described above, the following substituents are preferred.

R ¹ : hydrogen, straight or branched chain alkyl group having up to 6 carbon atoms, alicyclic hydrocarbon group having 5 to 7 carbon atoms or physiologically acceptable metal ion or ammonium ion, or ammonium derived from primary, secondary or tertiary amine ion.

R ² is a cycloalkyl group having 5 to 7 carbon atoms or a straight or branched alkyl group having up to 5 carbon atoms (where these alkyl groups are (a) fluorine, chlorine, or halogen, trifluoromethyl and / or alkyl having 1 to 6 carbon atoms). Or an α- or β-thienyl group or an α- or β-furyl group which may be substituted with alkoxy, or b) halogen, trifluoromethyl and / or alkyl or alkoxy having 1 to 6 carbon atoms or mono-, di, or It may be substituted with an oxyphenyl group or an α- or β-oxythienyl group which may be trisubstituted.

Among the substituents that can be used for R ² , the following are more preferred:

1-fluoromepentyl, 1-chloropentyl, 5--fluoromepentyl, 5-chloropentyl, 3-thienyl-2-ethyl, 2-thienyl-2-ethyl, 3- (2-chlorothienyl) -2-ethyl, 2- (5-chloro-thienyl) -2-ethyl, phenoxymethyl 3-chloro-phenoxymethyl, 3-trifluoromethyl-phenoxymethyl, 3-thienyloxymethyl, 2 -Thienyloxymethyl, 3- (2-chlorothienyl) -oxymethyl, 2- (5-chlorothienyl) -oxymethyl, 3-furyl-2-ethyl, 2-furyl-2-ethyl, cyclopentyl , Cyclohexyl and cycloheptyl.

Prostaglandin derivatives of the general formula (II) used as starting materials in the preparation process according to the invention can be prepared by methods analogous to those described in the literature. See JACS 91,5675 (1969), Tetrabedrom Lett, 1970, 311, Dutch Patents 7,206,361 and 7,209,758, German Patent Publications 2,524,955 and 2,742,407 (HOE77 / F 189).

Electrophilic reagents (e.g., iodine, iodine chloride, KI _S , N-bromosuccinimide and N-bromocampoimide, which react with τ-hydroxy-olipine to form tetrahydrofuran derivatives by ring closure) N-bromoimides, or 1,3-dibromo-5,5-dimethylhydantoin) are suitable for ring closure of the compound of formula (II) to obtain a compound of formula (III). The reaction proceeds preferably in an inert solvent (eg water, methylene chloride, chloroform, diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane). Heterogeneous or homogeneous solvent mixtures may be used. The reaction can be carried out between -70 and + 30 ° C. in the presence of an acid binder (eg calcium carbonate, sodium carbonate or sodium bicarbonate) if necessary.

In a preferred production method of the present invention, the compound of formula (II) is stirred with 1.2 to 3 equivalents of Kl ₃ in water of 0 to 10 ° C. in the presence of an inert gas and sodium carbonate, and the stirred Kl ₃ is removed with a sodium thiosulfate solution. Ring closure product III (x = 1) is extracted with chloroform. This product can be reacted again without any special purification.

If R ³ and / or R ⁴ represent a protecting group in the compound of formula (III), this group may be optionally removed.

Since the compound of formula (IV) is acid labile, it is suitable to remove protective groups such as acetal groups or tetrahydro, pyranyl groups under acid catalysis. It may be suitable to separate the protecting groups in an alcoholic or aqueous solution / organic solvent under acid catalysis. Suitable acids are dilute mineral or organic acids (eg P-toluene sulfonic acid, oxalic acid or acetic acid). If the protection group is an acyl group, this group can be removed in alkaline media.

The removal of HX from the compound of formula (III) to form the compound of formula (IV) proceeds under the action of a base in the presence or absence of a solvent.

Possible bases include inorganic and organic bases (e.g. alkali metal hydroxides or carbonates), alcoholates (e.g. sodium methylate or potassium tertiary butylate), amines (e.g. triethylamine, 4-dimethylaminopyridine , Dicyclohexylethylamine or 1,4-diazabicyclo [2,2,2] octane) or amidines (eg 1,5-diazabicyclo- [3,4,0] non-5-ene (DBN), 1,5-diazabicyclo [5,4,0] undec-5-yen (DBU)).

When R ³ and / or R ⁴ in the compound of formula (IV) is not hydrogen and is a protecting group (e.g. acyl group), this group is alcoholic or alcoholic using mild alkaline conditions, e.g. sodium carbonate or potassium carbonate. It can be removed in aqueous solution. This reaction is carried out at -10 to 30 ℃.

It is possible to simultaneously separate HX and protecting groups R ³ and / or R ⁴ (if they are acyl groups) from the compound of formula (III). Suitable reactions are, for example, reaction with alkali metal alcoholates (such as those containing sodium methylate in methanol) in alkali metal hydroxides or water or lower alkyl alcohols. Prostacyclin derivatives of general formula (I) can thus be obtained directly.

Compounds of formula (I) wherein R ¹ is an alkyl group can be obtained by esterifying a compound of formula (I) as R ¹ represents hydrogen or a cation and R ² is defined in compounds of formula (I). have. Since the enol ether structure is unstable in the prostacyclin molecule, esterification can only be used for esterification in which the process proceeds rapidly under mild conditions in neutral or weakly acidic media, or advantageously in alkaline media. For example, prostacyclin of formula (I) (R ¹ = hydrogen) using diazoalkanes of the general formula R ¹ -N ₂ (R ¹ = alkyl) at temperatures between -40 ° and + 20 ° C. Derivatives can be esterified and conventional solvents can be used (eg low molecular weight alcohols such as diethyl ether, tetra hydrofuran, chloroform or methanol). The resulting ester can be separated by a simple method of evaporating the solvent and can be purified by chromatography, if necessary. A preferred esterification process involves reacting a salt of the corresponding prostacyclin derivative I (R ¹ = cation) with an alkylating agent (R ¹ -X) in the presence of a base (eg metal alcoholate or metal carbonate) and in a suitable solvent. will be. Usable metal alcoholates include sodium methylate, sodium ethylate or potassium tertiary butyrate, and suitable carbonates include calcium carbonate or sodium bicarbonate. Suitable solvents that may be used include alcohols (e.g. methanol, or tert-butanol), ethers (e.g. tetrahydrofuran or 1,2-dimethoxyethane) and especially bipolar aprotic solvents (e.g. dimethyl) Formamide, dimethylsulfoxide, acetonitrile or N-methylpyrrolidone). For alkylating agents (R ¹ -X); X is preferably a bromine, iodine or sulfonic acid group.

Compounds of the general formula (I) wherein R ¹ is an alkyl group can be added to sodium hydroxide or potassium hydroxide in an alkaline medium, in a conventional manner, for example in a low molecular alcohol such as methanol or in an ether such as dimethoxy ethane or tetrahydrofuran. Can be used, if necessary, in the presence of water to saponify to afford the compound of formula (I) wherein R ¹ is hydrogen or preferably a cation. It is advantageous to use an equimolar amount or a slight excess of alkali metal hydroxide so that the solvent can be evaporated to obtain an alkali metal salt of the general formula (I) (R ¹ = alkali metal ion).

Alkali metal cations can be substituted for other cations on an ion exchanger by conventional methods. To do this, the alkali metal salt solution of the prostacyclin derivative of the present invention is passed through a column packed with a cation exchanger (eg Amberlite CG-50 or Dowex CCR-2).

The cation exchanger is charged with the desired cation (eg ammonium ion derived from primary, secondary or tertiary amines). The eluate is evaporated to yield the desired salt.

Compounds of formulas (II) and (III) are diastereomeric mixtures at the hydroxyl group position of carbon position 15 (named prostaglandin), for use in subsequent reactions in the form of pure α or β isomers or archeologically active coliforms. Can be. However, the stereoisomer or colon can be separated after any subsequent reaction step, which means that all reactions described can be carried out with diastereomeric mixtures, pure diastereomeric or optically active colon. If each reaction product is obtained in a form which is not pure enough to be used in the next reaction step, it is purified by column chromatography, thin layer chromatography or high pressure liquid chromatography.

In addition to the compounds mentioned in the examples, in particular the following compounds can be prepared by the process of the invention:

In a 20-Fluoro -PGI ₂ methyl ester, 16-PGI _2, 16- chloro -PGI _2-methyl ester, 17- (2-thienyl) -18,19,20- tree Nord PGI ₂ methyl ester, 17- (3 -(2-Chlorothienyl) -18,19,20-trinor PGI ₂ , 16-phenoxy-17,, 18,19,20-tetranor-PGI ₂ ethylester, 16- (3- (trifluoro Rommethyl-phenoxy) -17,18,19,20-tetranor-PGI ₂ methylester, 16- (2-thienyloxy) -17,18,19,20-tetranor-PGI ₂ , 17- ( 3-furyl) -18,19,20-trinor-PGI ₂ , 15-cyclopentyl-16,17,18,19,20-pentano-PGI ₂ , propylester and 15-cyclopentyl-16,17, 18,19,20-Pentanonor-PGI ₂

Compounds according to the invention

1) inhibitory effect on thrombo site aggregation,

2) relaxation of the vessel wall (especially coronary arteries),

3) It is characterized by having hypotension. Therefore, the compound of the present invention can be used as a drug

Possible unit doses that can be used for hypotension are 0.1 μg / kg to 10 μg / kg, 5 μg / kg to 100 μg / kg, and the daily dose is 0.001 mg / kg body weight, preferably 0.05 mg. Weight / kg to 1 mg / kg.

The same dose or smaller dose can be used for two different symptoms.

The compounds of formula (I) according to the invention can be used as free acids, but are preferably used in the form of physiologically acceptable inorganic or organic salts or as esters.

Acids and salts or esters may be in the form of these aqueous solutions or suspensions or pharmacologically acceptable organic solvents (eg monohydric or polyhydric alcohols such as ethanol, ethylene glycol or glyceryl; oil oils such as sunflower oil or cod liver oil); Ethers such as diethylene glycol dimethyl ether, polyethers such as leuethylene glycol) or in the presence of a pharmacologically acceptable polymerization excipient (eg polyvinyl pyrrolidone).

Formulations that can be used are conventionally available herbal extracts or injectable solutions and tablets and locally available formulations such as creams, emulsions, suppositories or aerosols.

Another way to use the novel compounds is to mix them with other active compounds. Other preferred materials that can be added are as follows:

Circulators in a broad sense include, for example, cardiac glycosides such as digitoxins, sympathetic stimulants such as surfprefen, β-sympathetic nerve blockers such as inderal, coronary dilators such as chromona or prenylamine, les Blood pressure lowering agents such as zerpin or clonidine, antiarrhythmic agents, blood flow stimulants, anticoagulants or fibrinolytic agents, diuretics such as furosemide, lipid-lowering substances or other agents used for senescence and other agents that affect metabolism, prostaglandins Or prostaglandin biosynthesis inhibitors, thromboxane synthase inhibitors, psychiatric agents and vitamins which are prostaglandin antagonists or non-steroidal anti-inflammatory agents.

Compounds of formulas (III) and (IV) are novel compounds and valuable intermediates for the preparation of compounds of formula (I).

Example 1

N-bromo succinimino 132 mg 16- (3-thienyloxy) -17,18,19,20-tetranor-PGF2α 11,15-bis-tetrahydropyranylether 360 mg tetrahydrofuran / chloro To a solution of 7 ml of water (1: 1), add to the solution under stirring in the presence of argon. After 2 hours, an aqueous solution of chloroform and sodium thiosulfate was added, dried over magnesium sulfate, and the organic layer was evaporated. The residue is warmed to 45 ° C. for 5 hours in the presence of argon in 5 ml of glacial acetic acid tetrahydrofuhan (3: 1: 1) and the solvent is evaporated in vacuo. The residue can be purified by column chromatography (using about 20 g of silica gel). As the eluent, ethyl acetate / glacial acetic acid (99: 1) is used.

NMR: see Example 1c.

200 mg of 16- (3-thienyloxy) -17,18,19,20-tetranor-ethyl ester (II) was dissolved in 1.5 ml of diethyl ether and 0.3 g of potassium bicarbonate in 1 ml of water was added, followed by argon. The mixture is cooled to 0 ° C. 5.4 ml of a solution of 2.5% iodine added to ether was added dropwise over 2 hours, followed by further stirring at 0 ° C. for 2 hours. After adding about 10 ml of ether, the organic layer is first washed with sodium thiosulfate solution, then with water, dried and evaporated. The reaction product is almost pure, but a small amount of impurities can be removed by chromatography on silica gel (eluent: cyclohexane / ethyl ether 2: 8).

Yield: 250 mg

Rf value (ethyl acetate): 0.54

NMR: see Example 1c.

16- (3-thienyl oxy) tetrahydro -17,18,19,20- Nord -PGF ₂ α methyl ester (Ⅱ) under the 200mg 50.8mg iodine, potassium iodide and 66mg sodium carbonate 42.4mg and argon present in the water 2ml Stir at 5-10 ° C. for 2 hours. Excess iodine is decolorized with sodium thiosulfate solution and the reaction product is extracted with chloroform. The organic layer is washed with water, dried and evaporated.

Yield: 244 mg

Rf value (ethyl acetate): 0.54

NMR: δ = 5.5 to 5.7 (m.2H), olefin quantum, 3.60 (s, 3H) O-CH3, 1.1-2.7 (m, 12H) -CH2- and> CH-, and 6.15-7.7 (m, 3H Thiophene.

In a similar reaction to Example 1c, the title compound is obtained from 17- (3-thienyl) -18,19,20-trinor-PGF ₂ α methylester (II).

NMR: δ = 1.1-2.9 (m, 16H) CH ₂ , and —CH—, 3.6 (s, 3H) OCH 3, 5.5-5.65 (m, 2H) olefin quantum, and 6.9-7.3 (m, 3H) thiophene .

Rf = 0.48 (ethyl acetate / acetic acid = 97.5 / 2.5)

In a similar manner to Example 1c, the title compound is obtained from 16- (3-chlorophenoxy) -17,18,19,20-tetranor-PGF ₂ αmethylester (II).

NMR: δ = 1.2-2.8 (m, 12H) CH ₂ , and -CH-, 3.7 (s, 3H) OCH ₃ , 4.0 (d, 2H) -CH--O-, 4.15 (1H) -CH-1 4.3-3.8 (m, 3H) -CH-OH, 5.7-5.9 (m, 2H) olefin quantum, and 6.7-7.4 (m, 4H) aromatic quantum.

Rf value (ethyl acetate): 0.35

A reaction similar to Example 1b) affords the title compound from 15- (cyclohexyl) -16,17,18,19,20-pentanonor-PGF 2α methyl ester (II).

NMR: δ = 0.8-2.8 (m, 23H) CH ₂ , and —CH—, 3.6 (s, 3H) OCH ₃ , 5.5-5.6 (m, 2H) olefin quantum.

In a similar manner to Example 1c), the title compound is obtained from 16-fluorine PGF ₂ αmethylester (II).

NMR: δ = 0.9-2.9 (m, 21H) -CH ₂ -and -CH-, 3.65 (s, 3H) OCH ₃ , 5.6-5.7 (m, 2H) olefin quantum.

In a similar manner to Example 1c), the title compound is obtained from 17- (3-furyl) -18,19,20-trinor-PGF ₂ αmethylester (II).

NMR: δ = 1.0-2.9 (m, 12H) CH ₂ , and -CH-, 3.6 (s, 3H) OCH ₃ , 5.5-5.6 (m, 2H) olefin quantum, 5.9-6.05 and 6.15-6.3 (m, 2H) aromatic quantum, 7.2-7.35 (m, 1H) aromatic quantum.

In a similar reaction to Example 1c), 17- (3-thienyl) -18,19,20-trinor-PGF ₂ αmethylester-11,15-bistetrahydropyranyl ether (II, R3 and R4 = Tetrahydropyranyl) to give the title compound.

Colorless oil, R _f value (ethyl acetate) 0.89

Example 2

300 mg of 16- (thienyloxy) -5-bromo-17,18,19,20-tetranor-PGI ₁ (Example 1a) was mixed with 224 mg of potassium tert-butyrate in 10 ml of tert-butanol in the presence of argon. Warm to 50 &lt; 0 &gt; C. After the mixture was stirred for 2 hours, the solvent was evaporated in vacuo, ice water and cold ether were added to the residue, and the aqueous layer was quickly adjusted to pH 5 using a cold solution of sodium dihydrogen phosphate. Cold ether containing excess diazomethane is immediately added to the ether layer. The mixture was stirred for 30 min at -5 ° C to 0 ° C, then the product, previously suspended in the ethyl acetate / triethylamine (95: 5) mixture for several hours, was purified on 15 g of silica gel. Eluent is ethyl acetate / triethylamine (98: 2).

R _f value = 0.15 (15α-epimer) (ethyl acetate / 0.5% concentration N (C ₂ H ₄ ) ₃ )

NMR: δ = 1.1-2.8 (m, 12H) CH ₂ , and CH, 2.8-3.0 (s, 2H) OH, 3.6 (m, 3H) OCH ₃ 5.6-5.7 (m, 2H) olefin quantum, 6.2-7.2 (m, 3H) thiophene.

290 mg of 5-iodo-17- (3-thienyl) -18,19,20-trinor-PGI ₁ -methyl ester (Example 1d) was charged with 1,5-diazabicyclo [5,4,0] Stir at 1-3 ml of deck-5-ene at room temperature. After 130 minutes, the reaction is over. 3 ml of ice water is added to the reaction solution and the product is extracted three times with ether. The organic layer was dried over anhydrous sodium sulfate and evaporated and then purified using silicacetate / triethylamine (98: 2) on silica gel by the method described in Example 2a.

R _f value = 0.17 (15α-epimer) (ethyl acetate / 0.5% concentration N (C ₂ H ₅ ) ₃ ).

Similar to Example 2b), but by reaction, the title compound is obtained from 5-iodo-16- (3-chlorophenoxy) -17,18,19,20-tetranor-PGI1 methylester (Example 1e).

NMR: δ = 3.6 (s, 3H) OCH ₂ , and CH, 4.0 (d, 2H) -CH ₂ O-, 5.7-5.9 (m, 2N) olefin quantum, 6.7-7.3 (m, 4H) aromatic quantum

R _f value = 0.22

Developer: Ethyl acetate / Et3N, 50/1

Thin plate: SiO 2 plate pretreated with ether / Et 3 N (3: 1).

A reaction similar to Example 2b) affords the title compound from 5-iodo-15-cyclohexyl-16,17,18,19,20-pentanonor-PGI ₁ methylester (Example 1f).

NMR: δ = O.8-2.8 (m, 23H) -CH ₂ , and CH, -CH-, 3.65 (s, 3H) OCH 3, 3.65-4.8 (m, 4H) -CHOH and -OO = CH, 5.5 -5.7 (m, 2) olefin quantum.

Example 2b) In a similar reaction, the title compound is obtained from 5-iodine-16-fluor-PGI ₁ , methyl ester (Example 1g).

NMR: δ = 0.9-2.8 (m, 22H) -CH ₂ and -CH-, 3.6 (s, 3H) OCH ₃ , 3.6-4.8 (m, 4H) -CH-OH and -0-C = CH, 5.5 -5.7 (m, 3H) olefin quantum.

In a similar reaction to Example 2b), the title compound is obtained from 5-iodo-17- (3-furyl) 18,19,20-trinor-PGI ₁ methylester (Example 1b).

NMR: δ = 1.0-2.85 (m, 12H) -CH ₂ and -CH-, 3.6 (s, 3H) OCH ₃ , 3.6-4.8 (m, 4H) -CHOH and -OC = CH, 5.9-6.05 and 6.15 -6.3 (m, 2H) aromatic quantum, 7.2-7.35 (m-1H) aromatic quantum.

5-iodo-17-3- (3-thienyl) -18,19,20-triol-PGI ₁ -methylester 11,15-bistetrahydropyranylether (Example 2b) The title compound is obtained from Example 1i).

Colorless oil, R _f value; 0.85 (ethyl acetate).

Example 3

268 mg (0.5 mmol) of 5-iodo-16- (3-thienyloxy) -17,18,19,20-tetranor-PGI ₁ methylester (Example 1c) are dissolved in 50 ml of 90% strength ethanol. 57.5 mg of sodium to 5 ml of ethanol is added to the solution while stirring. The mixture is stirred at 60 ° C. for 3 hours in the presence of argon, the solution is filtered using activated carbon and the solvent is removed from the filtrate under vacuum at −10 ° C. (freeze drying). The sodium salt of prostaglandin derivative is obtained as a colorless powder.

192 mg of pure 16- (3-thienyloxy) -17,18,19,20-tetranor-PGI ₁ methylester (Example 2a), 1.1 ml of 0.5 M potassium hydroxide solution and 2 ml of methanol at room temperature in the presence of inert gas Leave for 24 hours. Methanol is removed under vacuum and the aqueous solution of potassium salt is lyophilized. The potassium salt of prostacyclin derivative is obtained as a colorless powder.

50 mg of sodium salt of 16- (3-thienyloxy) -17,18,19,20-tetranor-PGI ₂ (Example 3b) on a column packed with 15 g of Amberlite CG-59 (triethylammonium form) Pour an aqueous solution of. The column is eluted with a 3% strength triethylammonium carbonate aqueous solution. The product is obtained as crystalline powder by lyophilization of the eluate (decomposition> 50 ° C).

d) the corresponding alkali metal salt or ammonium salt, if required by alkaline saponification of the ester from the compound of Examples 1a-1f or 2a-2f or by saponification of the ester simultaneously with the removal of HX, similar to Examples 3a-3c; It can be prepared by chromatography on an ion exchanger.

Claims (1)

The following compound of formula (II) is closed in the presence of a suitable electrophilic reagent to give a compound of formula (III), to give a compound of HX in the compound of formula (III) and protected under suitable neutral or alkaline conditions A process for the preparation of prostacyclin derivatives of general formula (I) by removal of groups.

In the above formula, R ¹ represents a straight or branched chain alkyl group having 6 or less carbon atoms, a straight or branched chain unsaturated aliphatic hydrocarbon group having 3 to 6 carbon atoms, an alicyclic hydrocarbon group having 3 to 7 carbon atoms, and an araliphatic hydrocarbon group having 7 to 9 carbon atoms, R ² is a cycloalkyl group having 3 to 7 carbon atoms or a straight or branched chain alkyl group having 8 or less carbon atoms, wherein these groups are (a) halogen or halogen, trifluoromethyl and / or alkyl in each case having 1 to 6 carbon atoms. Or α- or β-thienyl groups or α- or β-furyl groups, which may be mono-, di- or trisubstituted in the nucleus with alkoxy, or (b) halogen, trifluoromethyl and / or carbon atoms Alkyl or alkoxy having 1 to 6 may be substituted with an oxyphenyl group or α- or β-oxythienyl group, which may be mono-, di- or trisubstituted in the nucleus, R ³ and R ⁴ may be the same or different and represent hydrogen or a protecting group that can be easily removed, X represents chlorine, bromine or iodine.